Investigating the effects of chronic stress on hippocampal representations, synaptic connectivity and learning.

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Stress is the most prominent environmental factor contributing to the pathophysiology of psychiatric diseases such as depression, schizophrenia, anxiety and post traumatic stress disorder. The detrimental effects of stress on cognition include dysregulation of learning and memory. Consistently with this, in humans and mice, stress alters the structure and physiology of the hippocampus, which is a brain region key for episodic memory. Although stress induces profound structural changes in the hippocampus, it still is unclear what are the effects of such changes on the ability of hippocampal neuronal networks to learn and recall information. This is mainly because, until now, it has been impossible to track neuronal activity in the same subjects over the typical durations of chronic stress and to investigate neuronal structure longitudinally in the hippocampus. To overcome these obstacles, I propose to use head mounted wide field optical imaging to track activity of thousands of CA1 hippocampal pyramidal neurons in freely behaving mice and to study spatial representations upon chronic stress. This will enable us to investigate stress-induced changes in spatial codes and impairment in learning and memory in the same animals longitudinally. Moreover, I plan to combine head mounted wide field with two-photon optical imaging to track cellular activity and synaptic connectivity in the same hippocampal CA1 pyramidal neurons over weeks. This will enable us for the first time to study the relationship between neuronal connectivity and activity under baseline and stressful conditions. By investigating how stress changes the way in which the hippocampus represents space this project will shed light on the fundamental mechanisms of learning and memory which will be important not only for basic but also for translational science.